Emerging evidence suggests that dopamine D3 receptors may play a significant role in the behavioral effects of cocaine related to its abuse. To help evaluate this possibility a series of dopamine (DA) agonists varying in affinity and selectivity at the D3 receptor subtype were studied in squirrel monkeys trained to discriminate cocaine from vehicle. In drug substitution experiments, all DA agonists engendered dose-related increases in the percentage of cocaine-lever responses, reaching average maximums of 61 - 85%. The order of potency of the drugs for engendering cocaine-like stimulus effects (PHNO > NPA > 7-OH-DPAT r PD 128907 r quinpirole > bromocriptine) approximated their reported order of potency in both functional (DA-stimulated mitogenesis) and radioligand ([125I]iodosulpiride) binding assays in cells expressing cloned human D3 receptors, but not in cells expressing other DA receptor subtypes. In antagonism studies, the cocaine-like stimulus effects of the most selective of the D3 agonist, PD 128907, were attenuated by DA receptor antaonists with an order of potency (nemonapride > eticlopride > YM-43611) that corresponded more closely to their reported order of affinity at cloned human D3 than either D2 or D4 receptors. The effects of PD 128907 were not attenuated by the D1 receptor antagonist SCH 39166. In a final series of experiments, the discriminative stimulus effects of cocaine were enhanced in an additive manner by PD 128907, 7-OH-DPAT and quinpirole. The results support a role for D3 receptor mechanisms in the cocaine-like stimulus effects of D3-preferring agonists and suggest that similar mechanisms may contribute to the subjective effects of cocaine.